TALEN-Mediated Gene Editing of HBG in Human Hematopoietic Stem Cells Leads to Therapeutic Fetal Hemoglobin Induction
Elements within the γ-hemoglobin promoters ( and ) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH...
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| Published in | Molecular therapy. Methods & clinical development Vol. 12; pp. 175 - 183 |
|---|---|
| Main Authors | , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Limited
15.03.2019
American Society of Gene & Cell Therapy Elsevier |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2329-0501 2329-0501 |
| DOI | 10.1016/j.omtm.2018.12.008 |
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| Abstract | Elements within the γ-hemoglobin promoters (
and
) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the
promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous
promoters to de-repress fetal hemoglobin. Transfection of human CD34
cells with TALEN mRNA resulted in indel generation in
(43%) and
(74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34
cells
in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression
and
, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. |
|---|---|
| AbstractList | Elements within the γ-hemoglobin promoters (
and
) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the
promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous
promoters to de-repress fetal hemoglobin. Transfection of human CD34
cells with TALEN mRNA resulted in indel generation in
(43%) and
(74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34
cells
in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression
and
, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. Elements within the γ-hemoglobin promoters ( HBG1 and HBG2 ) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34 + cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34 + cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo , suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia.Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. Keywords: TALEN, hemoglobinopathy, HBG, hemoglobin, HPFH, SCD, sickle cell disease, thalassemia, gene editing, HSC |
| Author | Jacoby, Kyle Rawlings, David J. Scharenberg, Andrew Flowers, David A. Pattabhi, Sowmya Humbert, Olivier Bernstein, Irwin Lux, Christopher T. Yang, Julia G. Lee, Calvin Berger, Mason Nourigat, Cynthia Negre, Olivier Kiem, Hans-Peter |
| AuthorAffiliation | 2 Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA 6 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA 4 Department of Medicine, University of Washington, Seattle, WA 98195, USA 7 Department of Immunology, University of Washington, Seattle, WA 98195, USA 1 Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children’s Research Institute, Seattle, WA 98101, USA 3 bluebird bio, Inc., Cambridge MA 02142, USA 5 Department of Pathology, University of Washington, Seattle, WA 98195, USA |
| AuthorAffiliation_xml | – name: 2 Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA – name: 1 Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children’s Research Institute, Seattle, WA 98101, USA – name: 6 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA – name: 3 bluebird bio, Inc., Cambridge MA 02142, USA – name: 5 Department of Pathology, University of Washington, Seattle, WA 98195, USA – name: 7 Department of Immunology, University of Washington, Seattle, WA 98195, USA – name: 4 Department of Medicine, University of Washington, Seattle, WA 98195, USA |
| Author_xml | – sequence: 1 givenname: Christopher T. surname: Lux fullname: Lux, Christopher T. – sequence: 2 givenname: Sowmya surname: Pattabhi fullname: Pattabhi, Sowmya – sequence: 3 givenname: Mason surname: Berger fullname: Berger, Mason – sequence: 4 givenname: Cynthia surname: Nourigat fullname: Nourigat, Cynthia – sequence: 5 givenname: David A. surname: Flowers fullname: Flowers, David A. – sequence: 6 givenname: Olivier surname: Negre fullname: Negre, Olivier – sequence: 7 givenname: Olivier surname: Humbert fullname: Humbert, Olivier – sequence: 8 givenname: Julia G. surname: Yang fullname: Yang, Julia G. – sequence: 9 givenname: Calvin surname: Lee fullname: Lee, Calvin – sequence: 10 givenname: Kyle surname: Jacoby fullname: Jacoby, Kyle – sequence: 11 givenname: Irwin surname: Bernstein fullname: Bernstein, Irwin – sequence: 12 givenname: Hans-Peter surname: Kiem fullname: Kiem, Hans-Peter – sequence: 13 givenname: Andrew surname: Scharenberg fullname: Scharenberg, Andrew – sequence: 14 givenname: David J. surname: Rawlings fullname: Rawlings, David J. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30705922$$D View this record in MEDLINE/PubMed |
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| Keywords | thalassemia SCD TALEN HSC HPFH HBG gene editing hemoglobinopathy hemoglobin sickle cell disease |
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| Snippet | Elements within the γ-hemoglobin promoters (
and
) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell... Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression.... Elements within the γ-hemoglobin promoters ( HBG1 and HBG2 ) function to bind transcription complexes that mediate repression of fetal hemoglobin expression.... |
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| SubjectTerms | Binding sites CD34 antigen Cell differentiation Clonal deletion Deoxyribonucleic acid Design Disease DNA Fetuses Flow cytometry Gene deletion Gene silencing Genome editing Genotype & phenotype Hematopoietic stem cells Hemoglobin High-performance liquid chromatography Medical research Mutation Phenotypes Promoters Proteins Sickle cell disease Stem cell transplantation Stem cells Thalassemia Transcription activator-like effector nucleases Transcription factors Transfection Transplants & implants |
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| Title | TALEN-Mediated Gene Editing of HBG in Human Hematopoietic Stem Cells Leads to Therapeutic Fetal Hemoglobin Induction |
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